It is known that the receptor located in a neural cell membrane in a synapse stimulates nerve signals transmitted through G-protein linked receptors and ligand-gated ion channels with the help of neurotransmitter such as dopamine and serotonin. Part of a neurotransmitterreceptor is located in a presynaptic nerve cell membrane for reuptaking neurotransmitter or is located in a cell body for a negative feedback function. The targets to be coupled by a radiotracer generally used for evaluating the imagined transmission system might be the whole processes related with the creation, movement and decomposition of neurotransmitter. It is possible to image and quantify the functions of cranial nerves and the changes due to diseases by using enzyme involved in a synthesis of neurotransmitter, a post synaptic receptor isolated and coupled in a form of synapse, a transporter which reuptakes a neurotransmitter isolated in synapse through a presynaptic nerve terminal, and a radiotracer which is selectively coupled to enzyme which decomposes a neurotransmitter.
The radiotracer used for the image of a neurotransmitter receptor must have a high binding affinity and selectivity and must have less non-specific binding in tissues which does not have any receptor. In addition, it is required that the radiotracer must fast pass through a blood brain barrier, generating less metabolite after being administrated into blood, and the produced metabolite must be fast eliminated from the blood in order to prevent being reabsorbed into brain.
The radiotracer currently used in a clinic or aresearch can be classified into a SPECT for a radiotracer and a PET for a radiotracer depending on the kinds of labeled isotope. The tracer with radioisotopes such as 123I (t1/2=13 h) or 99mTc (t1/2=6 h), which has a relatively longer half life, for thereby obtaining a SPECT image. The SPECT disadvantageously has a poor accuracy in a resolution and quantification of the image as compared to the PET. Therefore, radiotracers are currently focused on the development of PET radiotracers which have PET isotope like 11C (t1/2=20 min) and 18F (t1/2=110 min).
The dopamine receptor antagonist [18F]fallypride, {(S)-N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[18F]-fluoropropyl)-2,3-dimethoxybenzamide}, which has the extremely selectivity and high affinity for D2 and D3 subtype and poor affinity for the D4 subtype, is currently being used as a potential dopamine D2/D3 receptor imaging agent by positron emission tomography (PET).
As the cortical dopamine function related with cognition in neuropsychiatric illness has been more importantly considered, [18F]fallypride has caught more attention with its capability of visualization of extrastriatal D2 receptors as well as striatal D2 receptors. In addition, the relatively longer half-life of radionuclide (fluorine-18, t1/2=110 min) in [18F]fallypride provides good prospects in assessing low concentration of extrastriatal dopamine D2/D3 receptors. Therefore, the efficient radiochemical synthesis of [18F]fallypride is important with the high radiochemical yield and specific activity for routine clinical research studies. As seen in the following reaction formula 1, the synthesis of [18F]fallypride can be conducted by labeling of fluorine-18 with tosyl-fallypride (tosylate precursor) (2) using phase-transfer catalyst.

In the preparation of [18F]fallypride, Mukgerjee and coworkers reported the moderate yields about 20-40% with 33-63 GBq/mol of specific activity and relatively long incorporation time of fluorine-18 with tosyl-fallypride about 30 min in manual synthesis. Moreover, the lengthy purification process of HPLC had to follow to avoid mass peaks due to significant thermal degradation of the precursor, the formation of the corresponding alcohol, or olefin resulting from elimination reactions, as well as other unidentified peaks in approximately 2 mg of precursor scales. In some cases, further purification of [18F]fallypride appears to be necessary in order to obtain higher specific activities.
The method for automatically synthesizing [18F]fallypride was proposed, which uses a RDS-112 CPCU (CTI) or TracerLab FX-FN (GE Healthcare). Although it has been shown using automated synthesis that [18F]fallypride can be prepared by one-step radiochemical synthesis with a tosylate precursor, the radiochemical yields are somewhat low (5-20%), for the same reason described above in manual synthesis. (Ansari et al., 2006. Comparison of three [18F]fallypride methods intended for automated remote chemistry modules. J. Nucl. Med. 47 (suppl), 159S Shiet al., 2002. Automated clinical production of F-18 radiopharmaceuticals with electrophilic or nucleophilic substitution in a custom manufactured fluorination module. J. Nucl. Med. 43 (suppl.), 1522S) Recently, microfluidic devices with milder reaction conditions have emerged to produce radiotracers for molecular imaging by microPET (Gillieset al., 2005. Microfluidic reactor for the radiosynthesis of PET radiotracers. Appl. Radiat. Isot. 64 (3), 325-332 Jeffery et al., 2004. Radiochemistry on microfabricated devices: Proof of principle. J. Nucl. Med. 45 (Suppl. 2), 51P Lee et al., 2005. Multistep synthesis of a radiolabeled imaging probe using integrated microfluidics. Science 310 (5755), 1793-1796 Liow et al., 2005. Preliminary studies of conducting high level production radiosynthesis using microfluidic devices. J. Label. Compd. Radiopharm. 48, (Suppl.), S28 Lu et al., 2009 Synthesis of [18F]fallypride in a micro-reactor: Rapid optimization and multiple-production in small doses for microPET studies. Curr. Radiopharm. 2 (1), 49-55 Lucignani, G., 2006. Pivotal role of nanotechnologies and biotechnologies for molecular imaging and therapy. Eur. J. Nucl. Med. Mol. Imaging. 33 (7), 849-851 Steel et al., 2007. Automated PET radiosyntheses using microfluidic devices. J. Label. Compd. Radiopharm. 50 (5), 308-311). It has several advantages including the use of lower amounts of precursor and base, easier and more efficient purification, relatively high conversion yield, and short preparation time. The successful production of [18F]fallypride with micro-reaction devices in small doses of about 0.5-1.5 mCi was reported (Lu et al., 2009 Synthesis of [18F]fallypride in a micro-reactor: Rapid optimization and multiple-production in small doses for microPET studies. Curr. Radiopharm. 2 (1), 49-55), although high-dose-scale production was not addressed. More recently, some groups have reported moderate radiochemical yields in automated [18F]fallypride production of about 20-40% (Ansari et al., 2006. Comparison of three [18F]fallypride methods intended for automated remote chemistry modules. J. Nucl. Med. 47 (suppl), 159S Kuhnast et al., 2009. Production of [18F]fallypride on a tracerlab FX-FN synthesizer. J. Label. Compd. Radiopharm. 52 (suppl.), 286S Lukic et al., 2009. Fully automated system for [18F]fallypride routine production with tracerlab MX module. J. Label. Compd. Radiopharm. 52 (suppl.), 315S Mock et al., 2009. Fully automated synthesis of [11C]fallypride and [18F]fallypride. J. Label. Compd. Radiopharm. 52 (suppl.), 258S Vuong et al., 2009. [18F]fallypride synthesis with protic solvent mixture. J. Label. Compd. Radiopharm. 52 (suppl.), 298S). In these studies, however, production proceeded at high temperatures (150-165° C.) or involved the use of an unusual microwave system in automatic devices. Moreover, various by-products were produced during HPLC purification as described above. The use of high base concentrations in the fluorine-18 labeling step is likely the main reason why various side products were generated, providing low radiochemical yield particularly in the case of base-sensitive tosyl-fallypride.
In automatic synthesis, QMAor Chromafix PS-HCO3 cartridge was frequently used in capture-release manner to extract fluorine-18 ion because fluorine-18 is produced in largely diluted 18O-enriched water. In that time, fluorine-18 could be released from polymer cartridge by elution with relatively large amounts of K2CO3/K2.2.2., CsCO3/K2.2.2., TBAOH, or TBAHCO3 etc. Such large amounts of base (>3 mg for K2CO3>30 μL for TBAHCO3) lead to more than the expected amounts of various side products, and hence require more quantity of precursor and diminish radiochemical yield and purity. Thus, the incorporation of fluorine-18 into base-sensitive [18F]fallypride has not been achieved in high radiochemical yields until now because fluorine-18 could not elute from ion exchange cartridge over 95% in relatively low base concentration (small amounts of phase-transfer catalyst).
For routine clinical use of [18F]fallypride, an automated preparation with a high radiochemical yield and purity are required.
The inventors of the present application demonstrated the minimization of base concentration when fluorine-18 was eluted from the ion exchange cartridge in radiosynthesis using the utility of a commercial TracerLab FXFN chemistry module and also described the production of [18F]fallypride in relatively high-doses with high specific activity, purity and shortened preparation time for routine clinical use, which resulted in the present invention.